Treatment of neurotic disorders

ABSTRACT

Use of escitalopram (the S-(+)-enantiomer of citalopram) or a pharmaceutically acceptable salt thereof for the preparation of a medicament useful in the treatment of neurotic disorders is provided, including anxiety states, in particular generalised anxiety disorder and social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder and panic attacks.

This application is a continuation of PCT/DK00/00377, filed Jul. 7,2000.

FIELD OF INVENTION

The present invention relates to the use of the compound escitalopram(INN-name), which is the S-enantiomer of the well-known antidepressantdrug citalopram, i.e.(S)-1-[3-(dimethyl-amino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile,or a pharmaceutically acceptable salt thereof for the preparation ofmedicaments for the treatment of neurotic disorders, including anxietystates and panic attacks.

BACKGROUND OF THE INVENTION

Citalopram is a well-known antidepressant drug that has now been on themarket for some years and has the following structure:

It is a selective, centrally acting serotonin (5-hydroxytyptamine; 5-HT)reuptake inhibitor, accordingly having antidepressant activities. Theantidepressant activity of the compound has been reported in severalpublications, eg. J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol.Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987,75, 478-486, and it is now marketed for the treatment of depression andpanic disorders. The compound has further been disclosed to show effectsin the treatment of dementia and cerebrovascular disorders, EP-A 474580.

Escitolopram and a method for its preparation are disclosed in U.S. Pat.No. 4,943,590. The stereo selectivity of citalopram, i.e. the5-HT-reuptake inhibition in the S-enantiomer, and accordingly, theantidepressant effect of said enantiomer is also disclosed. S-citalopramis now in development as an antidepressant.

Studies have shown that patients suffering from neurotic disordersincluding anxiety disorders, especially generalised anxiety, and panicattacks, in particular in association with agoraphobia, have a qualityof life impairment comparable with or greater than the disability foundin patients with alcoholism, schizophrenia or personality disorders.Furthermore, current treatments are not always effective or causeunacceptable side effects.

Consequently, there is a need for alternative therapies useful in thetreatment of neurotic disorders.

Escitalopram has now been found to show potent effects in models ofneurotic disorders such as anxiolytic effect and prominent effect in thetreatment of panic attacks and obsessive compulsive disorder.

DESCRIPTION OF THE INVENTION

According to the present invention, a novel use of escitalopram, namelyfor the preparation of a medicament useful in the treatment of neuroticdisorders is provided.

Throughout this specification and claims the term neurotic disorders isused to designate a group of mental disorders, including anxiety states,in particular generalised anxiety disorder and social anxiety disorder,post traumatic stress disorder, obsessive compulsive disorder and panicattacks.

The terms generalised anxiety disorder, social anxiety disorder, posttraumatic stress disorder and obsessive compulsive disorder are asdefined in DSM IV.

The phrase “panic attacks” contemplates treatment of any disease, whichis associated with panic attacks including panic disorder, specificphobias, social phobia and agoraphobia in which panic attacks occur.These disorders are further defined in the DSM IV. A panic attack is adiscrete period in which there is a sudden onset of intenseapprehension, fearfulness or terror, often associated with feelings ofimpending doom. During the attack, symptoms such as palpitations,sweating, trembling, sensations of shortness of breath, feeling ofchoking, chest pain or discomfort, nausea, feeling dizzy, feelings ofunreality, fear of losing control or going crazy, fear of dying,paresthesias and chills or hot flushes are present.

Panic disorders are characterised by recurrent unexpected panic attacksabout which there is a persistent concern. Agoraphobia is anxiety about,or avoidance of, places or situations from which escape might bedifficult or in which help may not be available in the event of a panicattack. Specific phobia and social phobia (together formerly simplephobia) are characterised by marked and persistent fear that isexcessive or unreasonable, cued by the presence or anticipation of aspecific object or situation (flying, heights, animals, seeing bloodetc.) or social performance situations.

The disorders in which panic attacks occur are differentiated from eachother by the predictability of the occurrence of the attacks, forexample, in panic disorder the attacks are unpredictable and notassociated with any particular event, whereas in specific phobia theattacks are triggered by specific stimuli.

The phrase “treatment of panic disorder” means a reduction in the numberor prevention of attacks and/or relief of the severity of the attacks.Similarly, the treatment of generalised anxiety disorder, social anxietydisorder, post traumatic stress disorder and obsessive compulsivedisorder include the treatment or prevention of these diseases, or therelief of the symptoms thereof.

According to the invention, escitalopram may be used as the base of thecompound or as a pharmaceutically acceptable acid addition salt thereofor as an anhydrate or hydrate of such salt. The salts of the compoundused in the invention are salts formed with non-toxic organic orinorganic acids, in particular the oxalate.

Escitalopram has been found to show prominent effects different from theeffects of the racemate in the “Inhibition of footshock-inducedultrasonic vocalisation in adult rats”—test, the “Mice Black and WhiteTest” setup, and in the polydipsia test. These models are standardanimal models for anxiolytic effect and effect on panic attacks and forobsessive compulsive disorder, respectively.

According to the invention, escitalopram or a pharmaceuticallyacceptable salt thereof may be administered in any suitable way e.g.orally or parenterally, and it may be presented in any suitable form forsuch administration, e.g. in the form of tablets, capsules, powders,syrups or solutions or dispersions for injection. Preferably, and inaccordance with the purpose of the present invention, the compound ofthe invention is administered in the form of a solid pharmaceuticalentity, suitably as a tablet or a capsule or in the form of asuspension, solution or dispersion for injection.

Methods for the preparation of solid pharmaceutical preparations arewell known in the art. Tablets may thus be prepared by mixing the activeingredients with ordinary adjuvants and/or diluents and subsequentlycompressing the mixture in a convenient tabletting machine. Examples ofadjuvants or diluents comprise: corn starch, lactose, talcum, magnesiumstearate, gelatine, lactose, gums, and the like. Any other adjuvant oradditive such as colourings, flavourings, preservatives, etc. may alsobe used provided that they are compatible with the active ingredients.

The compound of the invention is most conveniently administered orallyin unit dosage forms such as tablets or capsules, containing the activeingredient in a dose from about 1.0 mg to 50 mg, preferably 5 mg/day to40 mg/day, most preferably 10 mg/day to 20 mg/day.

The oxalate of escitalopram may be prepared as described in U.S. Pat. No4,943,590 and the base and other pharmaceutically acceptable salts maybe obtained therefrom by standard procedures.

Thus the acid addition salts used according to the invention may beobtained by treatment of escitalopram with the acid in an inert solventfollowed by precipitation, isolation and optionally re-crystallisationby known methods and if desired micronisation of the crystalline productby wet or dry milling or another convenient process, or preparation ofparticles from a solvent-emulsification process.

Pharmacological Tests

Escitalopram was tested in well recognised and reliable test models ofeffects on neurotic disorders. Citalopram-racemate was included forcomparison purposes.

The Footshock-induced Vocalisation Test in Adult Rats.

The footshock-induced vocalisation test in adult rats (described indetail in Sánchez C., Effect of serotonergic drugs on footshock-inducedultrasonic vocalization in adult male rats. Behav. Pharmacol. 1993;4:267-277) is a test for anxiolytic and anti-panic effects.

Experimental Procedure

Male rats (Wistar WU, Charles River, Germany), weighing 150-175 g at thebeginning of the study were used.

Briefly, test cages (22 cm×22 cm×22 cm) made of grey Perspex andequipped with a metal grid floor were used. Footshocks were deliveredfrom a two pole shocker and a microphone sensitive to ultrasounds in therange of 20-30 kHz was placed in the centre of the lid of the test cage.The ultrasounds were sent from the microphone to a preamplifier andconverted from AC signals to DC signals in a signal rectifier. Theaccumulated time, in which the voltage of the rectified signal waslarger than the voltage of a previously determined treshold level, wasrecorded.

Twenty-four hours before the first test session the animals were primed.A rat was placed in each test cage and received, immediately thereafter,four 1.0 mA inescapable footshocks each of a duration of 10 sec and withan intershock interval of 5 sec. The animals were left in the test cagefor 6 min after the last shock. On test days, drug or saline was given30 min before test. The rats received four 1.0 mA inescapable footshockseach of a duration of 10 sec. The intershock interval was 5 sec.Recording of ultrasonic vocalisation started 1 min after the last shockand lasted for 5 min. The total time spent on vocalisation was recorded.After a wash-out period of one week the rats were used in a new testsession. The rats were used for a total of 7-8 weeks. At each testsession, the animal groups were randomly allocated to treatment withsaline or test drug. Each treatment group consisted of 8 animals, onesaline and 2-4 drug treated groups were included at each session. Eachdrug was tested at least in two separate experiments with overlappingdoses.

Results

The experiments showed that the maximum effect was 60-70% inhibition forcitalopram-racemate whereas escitalopram was able to inhibitvocalisation completely.

Black and White Box Test

This is a test for anxiolytic effects. The test model is furtherdescribed in Sánchez, C. (1995) Pharmacol. Toxicol. 77, 71-78.

Test Procedure

Male mice (Lundbeck strain, Charles River, Germany) weighing 30-35 gwere housed in groups of 4 in macrolon cages type II under a reversed 12h day /night cycle (lights off 7 p.m.). The mice were adapted to thereversed light/dark cycle for at least 3 weeks prior to testing. Theroom temperature (21±2° C.), relative humidity (55±5%), and air exchange(16 times per h) were automatically controlled. The animals had freeaccess to commercial food pellets and water.

The test box used was designed as described by Sánchez (1995) (supra).Briefly, the test box (45 cm×27 cm×27 cm) was open-topped and dividedinto two compartments (ratio 2:3) by a partition which was black on theside facing the black compartment and white on the side facing the whitecompartment. The smaller chamber was made of black perspex. The largerchamber was made of white perspex except for the lowest 7.5 cm. Thispart was made of transparent perspex (outer walls) and black perspex(partition). The white compartment was connected to the blackcompartment by a 7.5 cm×7.5 cm opening in the partition. The floor ofthe white compartment was divided into 9 fields, and the floor of theblack was divided into 6 fields. The white compartment was illuminatedby means of a Schott KL 1500 electronic lamp emitting cold lightcorresponding to a light intensity of 560 Lux. The mouse test-system wasfully automated by 2 rows of 11 infrared light sources and photocells inthe transverse direction and 1 row of 16 in the longitudinal direction(lower row). The lower row of photocells (2 cm above cage floor)detected horizontal locomotor activity (crossing, entries, and time ineach compartment), whereas the upper row of photocells (5 cm above cagefloor) detected rearing activity. The accumulated data for 1 minintervals were recorded from 4 test boxed simultaneously and stored in aParadox data base.

The test boxes were placed in a dark and quiet room. The mice weretransported to the test room in a darkened container about 2 h beforetest. The test room was separated into two parts by a black curtain. Thedrug treatment took place in one part of the room using a minimum of redlight. After dosing, the mice were placed individually in macrolon typecages until test. The pretreatment time was 30 min. The test boxes wereplaced in the other part of the room. The test was started by placingthe mouse in the centre of the brightly-lit white compartment facing theopening to the black compartment. The test duration was 5 min and thenumber of rears and line crossings between squares in both the black andthe white compartment, number of entries into the black compartment andtime spent in the white compartment were assessed.

Results

Escitalopram showed prominent effects in this model.

Schedule-Induced Polydipsia

Food deprived rats exposed to a procedure in which food is deliveredintermittently will drink large amounts of water if given theopportunity to do so. This behavioural phenomenon is calledschedule-induced polydipsia and can be considered as an excessiveexpression of a normal behaviour. Schedule-induced polydipsia isregarded as a model of obsessive-compulsive disorder (Woods et al.1993).

Test Procedure

Male wistar rats (Møllegard) housed in pairs and kept on afood-restricted diet (80% of normal body weight) for 2 weeks before thestart of testing and throughout the duration of testing. To inducepolydipsia rats were placed in test chambers where a pellet dispenserautomatically dispensed one 60 mg food pellet every 60 seconds. Waterwas available at all times in the test chamber. Rats were tested 4-5times per week, after 3-4 weeks training 70% of the rats weredrinking >10 ml per 30 min test session.

Once the rats had attained a steady drinking level compounds could betested. Citalopram (40 mg/kg) or Lu 26-054 (20 mg/kg) were administeredorally 60 min prior to testing and at 10:00 on the non-test days. Thewater intake was presented as a percentage of the pre-dosing (baseline)level.

Results

Escitalopram produced a significant reduction in water intake, whereascitalopram was without effect.

All these studies show that escitalopram has potent anti neuroticdiseases effects, in particular anxiolytic effects and effects on panicattacks and obsessive compulsive disorder.

1. A method of treating panic attacks in a patient in need thereof, saidmethod comprising administration of a pharmaceutically effective amountof escitalopram or a pharmaceutically acceptable salt thereof to thepatient.
 2. The method of claim 1, wherein the pharmaceuticallyeffective amount of escitalopram or a pharmaceutically acceptable saltthereof is in a unit dose form.
 3. The method of claim 1, wherein themethod comprises administering 1.0 to 50 mg/day of escitalopram or apharmaceutically acceptable salt thereof.
 4. The method of claim 1,wherein the method comprises administering 5 to 40 mg/day ofescitalopram or a pharmaceutically acceptable salt thereof.
 5. Themethod of claim 1, wherein the method comprises administering 10 to 20mg/day of escitalopram or a pharmaceutically acceptable salt thereof. 6.The method of claim 1, wherein said panic attacks are associated withpanic disorder.
 7. The method of claim 1, wherein said panic attacks areassociated with specific phobias.
 8. The method of claim 1, wherein saidpanic attacks are associated with social phobia.
 9. The method of claim1, wherein said panic attacks are associated with agoraphobia.
 10. Themethod of claim 6, wherein the pharmaceutically effective amount ofescitalopram or a pharmaceutically acceptable salt thereof is in a unitdose form.
 11. The method of claim 6, wherein the method comprisesadministering 1.0 to 50 mg/day of escitalopram or a pharmaceuticallyacceptable salt thereof.
 12. The method of claim 6, wherein the methodcomprises administering 5 to 40 mg/day of escitalopram or apharmaceutically acceptable salt thereof.
 13. The method of claim 11,wherein the method comprises administering 10 to 20 mg/day ofescitalopram or a pharmaceutically acceptable salt thereof.
 14. Themethod of claim 7, wherein the pharmaceutically effective amount ofescitalopram or a pharmaceutically acceptable salt thereof is in a unitdose form.
 15. The method of claim 7, wherein the method comprisesadministering 1.0 to 50 mg/day of escitalopram or a pharmaceuticallyacceptable salt thereof.
 16. The method of claim 7, wherein the methodcomprises administering 5 to 40 mg/day of escitalopram or apharmaceutically acceptable salt thereof.
 17. The method of claim 7,wherein the method comprises administering 10 to 20 mg/day ofescitalopram or a pharmaceutically acceptable salt thereof.
 18. Themethod of claim 8, wherein the pharmaceutically effective amount ofescitalopram or a pharmaceutically acceptable salt thereof is in a unitdose form.
 19. The method of claim 8, wherein the method comprisesadministering 1.0 to 50 mg/day of escitalopram or a pharmaceuticallyacceptable salt thereof.
 20. The method of claim 8, wherein the methodcomprises administering 5 to 40 mg/day of escitalopram or apharmaceutically acceptable salt thereof.
 21. The method of claim 8,wherein the method comprises administering 10 to 20 mg/day ofescitalopram or a pharmaceutically acceptable salt thereof.
 22. Themethod of claim 9, wherein the pharmaceutically effective amount ofescitalopram or a pharmaceutically acceptable salt thereof is in a unitdose form.
 23. The method of claim 9, wherein the method comprisesadministering 1.0 to 50 mg/day of escitalopram or a pharmaceuticallyacceptable salt thereof.
 24. The method of claim 9, wherein the methodcomprises administering 5 to 40 mg/day of escitalopram or apharmaceutically acceptable salt thereof.
 25. The method of claim 9,wherein the method comprises administering 10 to 20 mg/day ofescitalopram or a pharmaceutically acceptable salt thereof.